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Widespread transcription at neuronal activity-regulated enhancers
Tae-Kyung Kim1,9,10, Martin Hemberg2,9, Jesse M. Gray1,9, Allen M. Costa1, Daniel M. Bear1, Jing Wu3, David A. Harmin1,4, Mike Laptewicz1, Kellie Barbara-Haley5, Scott Kuersten6, Eirene Markenscoff-Papadimitriou1,10, Dietmar Kuhl7, Haruhiko Bito8, Paul F. Worley3, Gabriel Kreiman2 & Michael E. Greenberg1
Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA
Department of Ophthalmology, Children’s Hospital Boston, Center for Brain Science and Swartz Center for Theoretical Neuroscience, Harvard University, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA
Children’s Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
Molecular Genetics Core facility, Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
Epicentre Biotechnologies, 726 Post Road, Madison, Wisconsin 53713, USA
Institute for Molecular and Cellular Cognition (IMCC), Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Falkenried 94, 20251 Hamburg, Germany
Department of Neurochemistry, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
These authors contributed equally to this work.
Present addresses: University of Texas Southwestern Medical Center, Department of Neuroscience, 5323 Harry Hines Blvd, Dallas, Texas 75390-9111, USA (T.-K.K.); Graduate Program in Neuroscience, University of California San Francisco, 1550 4th Street, San Francisco, California 94158, USA (E.M.-P.).
We used genome-wide sequencing methods to study stimulus-dependent enhancer function in mouse cortical neurons. We identified ~12,000 neuronal activity-regulated enhancers that are bound by the general transcriptional co-activator CBP in an activity-dependent manner. A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4. The level of eRNA expression at neuronal enhancers positively correlates with the level of messenger RNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. These findings reveal that a widespread mechanism of enhancer activation involves RNAPII binding and eRNA synthesis.
